Two major lineages of mature alpha-beta T cells can be distinguished on the basis of their differential expression of the CD4 and CD8 glycoproteins. These molecules are called coreceptors because they facilitate antigen recognition by the T cell receptor (TCR) through direct interactions with MHC class II and class I proteins, respectively. In the absence of coreceptor activity by CD4 or CD8, both the positive selection of thymocytes and the antigen responses of T cells can be highly inefficient. The proposed studies address the characteristics that distinguish a minor fraction of CD4 lineage T cells that can complete development in mice that are congenitally deficient in CD4 expression. The experiments will test the hypothesis that the absence of CD4 selects for CD4 lineage T cells which express TCRs that bind with high affinity to peptide/MHC class II complexes. Knowledge of how cells can circumvent the need for the CD4 coreceptor will provide insight into the normal function of this molecule in thymocyte development and T cell activation. In other studies, the expression of CD4 will be tightly regulated using conditional and tissue specific transgenic systems. These experiments will permit a direct evaluation of the role that CD4 plays in the antigen reactivity and functional differentiation of T cells. Overall, the proposed studies will contribute to a better understanding of the function of the CD4 molecule and the degree to which its expression is required for healthy and effective immune responses. These studies have bearing on the applicability of the CD4 molecule as a potential target for therapeutic intervention in autoimmune and viral diseases such as AIDS.